Reverse transcriptase (RT) mutations can render HIV resistance to various nucleoside and non-nucleoside anti-HIV agents. More and more drug resistant HIV-1 strains are being isolated or mutants constructed and characterized in terms of genotype, replicative capability, and virulence. This study targets strategies for selecting the most effective combinations of two or more anti-HIV agents and the assessment of the consequence of multi-drug mutations of the RI-POL gene. In this project, we will extend our studies on wild type and AZT resistant HIV strains to include a collection of genetically defined variants obtained in-house and from Drs. D.D. Richaman (San Diego) and M.S. Hirsch (Boston). Aim I is to determine kinetic and pharmacodynamic parameters of nucleoside and NNRT inhibitors on RTs and on HIVs, both wild type and mutated forms. These studies will include replication and infectivity of mutated HIV-1 variant, template-primer and substrate specificity, and infectivity constants for RTs, and drug susceptibility and resistance for HIVs. Aim II is to quantify the effects of multiple drug combinations (three or more drugs) against a series of genetically defined HIV strains with respect to replication and infectivity in acute and chronic infections, and in acute and chronic drug exposures. Synergism, and additive or antagonistic effects will be quantified. Aim III will continue our work with computer software for combination- index and dose-reduction index methodology from two to five drugs i anti- HIV drug combination studies. The analysis will include affinity constant sort the polymerase catalysis and nucleotide bindings as well as simulation of resistance at different effect of levels. These results are expected to define new approaches to multidrug-therapy of AIDS.